Salts of dibenzyl beta-halopropylamines



Patented Apr. 13,1954

SALTS OF DIBENZYL BEilk-HALOPRQPYL- AMINES William S. Gump, Upper Montclair, and Edward Joseph Nikawitz, lassaic, N. 5., assignors toThe 'Givaudan Corporation, New York, N. Y., a corporation of New Jersey No Drawing. Continuation of application .Serial No. 84,475, March 30, 1949. This application October 9, 1951, "Serial No. 725L578 8 Glaims.

This inventim relates to novel salts-of aromatic haloamines.

These novel chemicals are salts of dibenzyl betahaloalkylamines in which the halogen radical is attached to a non-terminal carbon atom of the .alkyl group. We have found that especially advantageous properties are possessed by the salts set forth above when the number of carbon atoms in the alkyl group dos not exceed six.

Assorne specific members of the novel chemical compounds disclosed herein the following may be noted:

Dibenzyl hetachloropropylamine hydrochloride dibenzyl beta-chlorobutylamine hydrochloride .Om. t1

dibenzyl beta chloro beta 'methylpropylamine hydrochloride and the corresponding bromine analogs.

in general, the novel "salts of this invention may be prepared by reacting an equivalent amount of inorganic or organic acids with the corresponding amines, preferably in some cases under .anhydrous or substantially anhydrous conditions. The amines may be prepared by reacting the corresponding hydro'halides with at least an equivalent amount of alkaline material, such as, for example potassium carbonate. The hydrohalides may :be prepared in general :by reacting the beta-alcohols of the amines with thionyl chloride, thionyl bromide, or hydrogen bromide.

The new salts of this invention are crystalline solids under usual atmospheric conditions and in general are soluble in alcohols and glycols, diflicultly soluble "in water and insoluble in ether and hydrocarbons. The amines are in general high boiling liquids, varying in color from water-white to yellow. They are not soluble in water, but dissolve in ethyl alcohol, propylene glycol, and organic solvents generally.

Our novel chemical compounds exhibit unex til pected and desirable medicinal properties, for example, as sympatho'lyisic and adrenoly-tic agents. For therapeutic purposes these novel compounds may be administered orally or parenteral-1y, and may be employed as tablets or in capsules or in solutions. In addition to their therapeutic properties our novel compounds are useful in organic chemical synthesis.

While our invention comprehends asal-ts' of the amines set forth above and acids general, "we prefer to employ those acids having an ionization constant of at least about 1X11)" at normal room temperature (about 25 0.). Examples of some suitable organic :acids are picnic, trichloroacetic, oxalic and maleic acids. Examples of some suitable :inorganic acids are hydrochloric, hydrobrom-ic, sulfuric, phosphoric -(first hydrogen), perchloric, nitric and iodic acids.

In order to illustrate this invention more fully but Without thereby limiting it, the following examples are given.

EXAMPLE 1 Preparation of dibenzyl beta-ch-ZoropropyZam-me hydrochloride Into 150 grams of isopropanolamine,. heated to C., were dropped understirring 253 grams of benzyl chloride during two hours; the mixture was then kept at 100 C. to C'., for five hours. A concentrated aqueous solution of 100 grams of sodium hydroxide was then added and the reaction product extracted with 600 grams of benzene. The benzene solution was washed with water, dried over anhydrous sodium sulfate and distilled. After removal of the benzene, the residual oil was distilled in vacuo and 168 grams of dibenzylamino isopropanol, boiling point 170 C. to C./4 mm., were collected.

Dibenzy'lamino isopropanol (127 grams) Were dissolved in 100 ml. of chloroform and cooled in an ice salt bath. To this solution, 70' grams of th'i'onyl chloride in 100 ml. of chloroform were added under stirring during two hours. Stirring was then continued for another three hours under cooling. The reaction mixture was allowed to stand over night. The chloroform was distilled off, applying low vacuum at the end. Ethanol (50 ml.) was added and the mixture evaporated to "dryness .in vacuo. The crystalline residue was dissolved in 80 m1. of isopropanol and the solution purified by addition of 2 grams of decolorizing carbon and refluxing for thirty minutes. The filtered and cooled solution was brought to crystallization by adding isopropyl ether. Ninety-two 55 grams of white crystals, melting at 165 C. to

3 167 0., were obtained. This is dibenzyl-betachloropropylamine hydrochloride.

Parenteral administration in man: this compound is dissolved in propylene glycol (sterile technic) to the extent of 5 per cent. It is stable in this solvent if the solution is acidified with concentrated hydrochloric acid, U. S. P. (2 ml. per 1000 ml. of solution). Injection is made slowly intravenously (either by syringe technic directly or by injection into the tubing of an intravenous saline or glucose infusion) after dilution with 0.9 per cent sodium chloride solution to at least 1:10. Evidence of physiological effect can usually be detected within ten to thirty minutes, as indicated by paralysis of adrenergic excitatory efiector cells. For example, the pupils become constricted, the heart and blood vessels do not respond as before to sympathetic nerve impulses or to administered epinephrine, etc. Dosage: 5 to mg./kg. per single dose. Efiects may last several days.

Efiective oral doses are in the neighborhood of five times the parenteral dose. The action takes approximately an hour to become manifested and persists for days, even after a single dose.

EXAMPLE 2 Preparation of dibenzyl beta-chlorobutyldmine hydrochloride (1-dibenzyZa.mino-2-chlorobu tdne' hydrochloride) (d) PREPARATION OF l-DIBENZYLAMINO-B-BUTEN- lization raised the melting point to 157 C. to

158 0. (closed capillary).

AhaL-Calcd. for C1sH22NOC1: Cl, Found: Cl. 11.60.

(b) PREPARATION N OL HYDROCHLORIDE Seventeen and five-tenths grams (.065 m.) of

1-dibenzylamino-3-buten-2-ol was dissolved in 50 cc. of alcohol and hydrogenated in the presence of Raney nickel catalyst at an initial pressure of 50 pounds per square inch. The, calculated amount of hydrogen was taken up in twenty minutes. The solution was filtered free of catalyst and the solvent distilled at atmospheric pressure. colorless oil, boiling point 156 .C. to l60 C./2.mm. It weighed 14 grams (80% of the theoretical). f The oil was dissolved in 100 ml. of ether and treated with dry hydrogen chloride. The salt was collected, dissolved in 75 ml. of alcohol, the solution was filtered and 50 ml..of ether was added. Ten grams of solid, melting point 176C. to 178 C., separated on cooling. After another recrystallization from alcohol-ether, the hydrochloride melted at 177 C. to 179 C. (closed capillary).

AnaZ.Calcd. for CIGHMCINOZ C1, 11.57. Found: Cl, 11.52.

OF l-DIBENZYLAMINO-2-BUTA- The product distilled as a (o) PREPARATION OF l-DIBENZYLAMINO-Z-CHLO ROBUTANE HYDROCHLORIDE A solution of 42 grams (0.13 m.) of l-dibenzylamino-Z-butanol hydrochloride in 50 ml. of dry chloroform was cooled in an ice bath while 31 grams (0.26 m.) of thionyl chloride in 50 ml. of chloroform were added. A reflux condenser carrying a calcium chloride tube was attached to the flask and the solution was heated by a water bath at 60 C. to 65 C. for one and one-half hours. The condenser was then set for downward distillation and the solvent was removed in vacuo. Approximately 200 ml. of ether was added to the residual syrup which solidified on stirring and cooling. The solid was collected, dissolved in 100 ml. of chloroform followed by 300 ml. of ether.- On cooling, 41 grams of a solid, melting point 141 C. to 143 0., were deposited. After recrystallization from alcohol-ether the hydrochloride weighed 28 grams (67%) and melted at 149 C. to 151 C. (closedcapillarylf AnaZ.-Calcd. for C18H23NC12I c, 66.66; ,-'7".:14i or 10.94. Found; C, 66.82; H, 7.06; 01, 10.98.

EXAMPLE 3 Preparation of dibenzyl beta-ohZoro-beta-mcth ylpropylamine hydrochloride (I-dibenzylamino-Z-methyZ-Z-chloropropcme hydrochloride) (a) PREPARATION OF 2-DIBENZYLAMINO-2-METH- YL-l-PROPANOL HYDROCHLORIDE.

anhydrous sodium carbonate were'added andthe' temperature was maintained at C.to C. for two hours. Water was added to the cooled reaction mixture and the organic layer separated. Three ether extracts of the aqueous solution were combined with the original organic layer and dried over anhydrous potassium carbonate; The solution was filtered and the solventremoved by'. distillation at atmospheric pressure. Distillation of the residue yielded 48% of-2-dibenzylamino- 2-methyl-1-propanol, boiling point 182 C. to

' 220 C./11 mm, which solidified in the receiver.

After recrystallization from alcohol, it melted at 76 C.t078C. w I AnwL-Calcd. for CiaHzsON: c, 80.25; H, 8.61. Found: C, 80.22; H, 8.62. i a

The hydrochloride was prepared in ether sol'u-f tion and recrystallized from alcohol-acetone mixture. It melted at 137 C. to 138 C. AnaL-Calcd. for C1sH24NOCl: 01, 11.57. Found: Cl,11.57. Y a

(b) PREPARATION OF l-DIBENZYLAMINOQ-METH; YL-2-CHLOROPROPANE HYDROCHLORIDE Fourteen grams (0.045 m.) of 2-diloenzylaimin0-I 2-methyl-1-propanol hydrochloride and 21 grams (0.180 m.) of thionyl chloride weremix'ed and heated under reflux for two hours. Excess thionylchloride was evaporated in vacuo at 30 :C. to 40 C., 25 ml. of benzene was added and the mixture again evaporated .to dryness. The solid grams, melting point 151 Otto 155 1?. (closed capillary). After another recrystallization from alcohol-ether the material weighed 12 grams (70% yield), melting point 152 C. to 154 '0. (closed capillary). Another preparation gave a similar yield.

AnaZr-Calcd. for C1sH2aNC122 C, 66.66; H, 7.14; Cl, 10.93. Found: C, 66.90; H, 7.62; CI, 11.01.

EXAMPLE 4 Dibenzyl beta-bromopropz Zamine hydrobromide Dibenzylamino isopropanol (51.0 grams), dissolved in 100 m1. of chloroform, was brought to reaction with 50.0 grams of thionyl bromide dissolved in 100 ml. of chloroform by adding the thionyl bromide during 2 hours under stirring to the ice-cooled aminoalcohol solution. The reaction mixture was allowed to remain at room temperature for 12 hours. After removal of the chloroform by distillation, the residue was refluxed with 100 ml. of alcohol in the presence of some decolorizing carbon, the solution was filtered and 550 ml. of ethyl ether added. The crystalline product was filtered off and another crystallization from alcohol (80 ml.) -ether (500 ml.) yielded 21.5 g. of white crystals, M. P. 144-146.

AnaL-Calcd. for CmI-IzrNBrz: Br (ionized), 20.0; Br (total), 40.0. Found: Br (ionized), 20.0; Br (total), 40.1.

It will be noted, as in Example 3, that when two substituents are present on the carbon atom adjacent to the nitrogen atom in the alcohol precursor, treatment with thionyl chloride causes a rearrangement of the skeletal carbon structure to form the 6,6-di-substituted-B-haloethylamine.

This application is a continuation of our copending application, Serial No. 84,475, filed March 30, 1949, which is a continuation in part of our therewith co-pending application, Serial No. 645,- 964, filed February 6, 1946, both of which applications now are abandoned.

The foregoing illustrates the practice of this invention, which however, is not to be limited thereby but is to be construed as broadly as permissible in view of the prior art and limited solely by the appended claims.

6 We claim: 1. Acid addition salts of amines having the following formula:

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,537,988 Goodman et a1. Jan. 16, 1951 2,602,040 Goodman et a1. July 1, 1952 FOREIGN PATENTS Number Country Date 538,456 Germany Oct. 29, 1931 550,762 Germany Apr. 28, 1932 

1. ACID ADDITION SALTS OF AMINES HAVING THE FOLLOWING FORMULA: 